Therapy For Subarachnoid Hemorrhage Research Articles

Brain-targeted ursolic acid nanoparticles for anti-ferroptosis therapy in subarachnoid hemorrhage

BackgroundSubarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy.MethodsSAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis.ResultsWe successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway.ConclusionsBrain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal.Graphical

Mesenchymal stem cells-derived therapies for subarachnoid hemorrhage in preclinical rodent models: a meta-analysis

BackgroundMesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have emerged as potential novel therapies for subarachnoid hemorrhage (SAH). However, their effects remain incompletely understood. We aim to comprehensively evaluate the effect of MSCs-derived therapies in rodent models of SAH.MethodsWe searched PubMed, EMBASE, and Web of Science up to September 2021 to identify studies that reported the effects of MSCs or MSCs-derived EVs in a rodent SAH model. Neurobehavioral score was extracted as the functional outcome, and brain water content was measured as the histopathological outcome. A random-effects model was used to calculate the standardized mean difference (SMD) and confidence interval (CI).ResultsNine studies published from 2018 to 2021 met the inclusion criteria. Studies quality scores ranged from 5 to 10, with a mean value of 7.22. Our results revealed an overall positive effect of MSCs and MSCs-derived EVs on the neurobehavioral score with a SMD of − 2.21 (95% CI − 3.14, − 1.08; p < 0.0001). Meanwhile, we also found that MSCs and MSCs-derived EVs reduced brain water content by a SMD of − 2.09 (95% CI − 2.99, − 1.19; p < 0.00001). Significant heterogeneity among studies was observed, further stratified and sensitivity analyses did not identify the source of heterogeneity.ConclusionsOur results suggested that MSCs-derived therapies prominently improved functional recovery and reduced brain edema in the rodent models of SAH. Notably, the limitations of small sample size should be considered when interpreting the results, and large animal studies and human trials are needed for further investigation.

Neuroprotective Effects of Hesperidin on Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage in Rats: Biochemical, Pathologic, and Histomorphometric Analysis

We examined the protective effects of hesperidin on cerebral vasospasm by establishing an experimental rat model of subarachnoid hemorrhage and performing biochemical, pathologic, and histomorphometric analysis on these data. Forty albino Wistar rats were randomly divided into 5 groups of n= 8 in each: group (G)1, no experimental interventions; G2, subjected to subarachnoid hemorrhage; G3, subjected to subarachnoid hemorrhage and administered saline (100 mg/kg); G4, subjected to subarachnoid hemorrhage and treated with low-dose hesperidin (50 mg/kg); and G5, subjected to subarachnoid hemorrhage and treated with high-dose hesperidin (100 mg/kg). Subarachnoid hemorrhage was created by injecting 0.15 cc of autologous blood taken from the rat-tail artery and injected into the cisterna magna from the craniocervical junction. Drugs were administered intraperitoneally as twice daily doses for 48 hours. Rats were euthanized at the end of this period. No statistically significant decrease was observed in malondialdehyde levels, which is the end-product of lipid peroxidation, among the drug groups (G4 and G5). Thin sections prepared from the basilar artery were examined morphologically. Severe luminal narrowing and vessel-wall thickening were observed in the subarachnoid hemorrhage groups (G2, G3). In the hesperidin-administered groups (G4, G5), it was determined that vessel wall thickness measurements revealed thinner walls than in the subarachnoid hemorrhage groups (G2, G3) and the luminal diameters were significantly larger than in the subarachnoid hemorrhage groups (G2, G3). These findings suggest that hesperidin has no effect on malondialdehyde-associated lipid-peroxidation activity; however, it might be useful in subarachnoid hemorrhage therapy because of its beneficial effects on vessel wall thickness and luminal diameters.

Intranasal Stem Cell Treatment as a Novel Therapy for Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) represents a major health problem in Western society due to high mortality and morbidity, and the relative young age of patients. Currently, efficacious therapeutic options are very limited. Mesenchymal stem cell (MSC) administration has been shown to improve functional outcome and lesion size in experimental models of stroke and neonatal hypoxic-ischemic brain injury. Here, we studied the therapeutic potential of intranasally administered bone marrow-derived MSCs relatively late postinsult using a rat endovascular puncture model for SAH. Six days after induction of SAH, rats were treated with MSCs or vehicle through nasal administration. Intranasal MSC treatment significantly improved sensorimotor and mechanosensory function at 21 days after SAH. Gray and white matter loss was significantly reduced by MSC treatment and the number of NeuN+ neurons around the lesion increased due to MSC treatment. Moreover, intranasal MSC administration led to a sharp decrease in SAH-induced activation of astrocytes and microglia/macrophages in the lesioned hemisphere, especially of M2-like (CD206+) microglia/macrophages. Interestingly, MSC administration also decreased SAH-induced depression-like behavior in association with a restoration of tyrosine hydroxylase expression in the substantia nigra and striatum. We show here for the first time that intranasal MSC administration reverses the devastating consequences of SAH, including regeneration of the cerebral lesion, functional recovery, and treatment of comorbid depression-like behavior.

Hydrogen Sulfide Ameliorates Early Brain Injury Following Subarachnoid Hemorrhage in Rats.

Increasing studies have demonstrated the neuroprotective effect of hydrogen sulfide (H2S) in central nervous system (CNS) diseases. However, the potential application value of H2S in the therapy of subarachnoid hemorrhage (SAH) is still not well known. This study was to investigate the potential effect of H2S on early brain injury (EBI) induced by SAH and explore the underlying mechanisms. The role of sodium hydrosulfide (NaHS), a donor of H2S, in SAH-induced EBI, was investigated in both in vivo and in vitro. A prechiasmatic cistern single injection model was used to produce experimental SAH in vivo. In vitro, cultured primary rat cortical neurons and human umbilical vein endothelial cells (HUVECs) were exposed to OxyHb at concentration of 10μM to mimic SAH. Endogenous production of H2S in the brain was significantly inhibited by SAH. The protein levels of the predominant H2S-generating enzymes in the brain, including cystathionineb-synthase (CBS) and 3-mercaptopyruvate sulfur transferase (3MST), were also correspondingly reduced by SAH, while treatment with NaHS restored H2S production and the expressions of CBS and 3MST. More importantly, NaHS treatment could significantly attenuate EBI (including brain edema, blood-brain barrier disruption, brain cell apoptosis, inflammatory response, and cerebral vasospasm) after SAH. In vitro, H2S protects neurons and endothelial function by functioning as an antioxidant and antiapoptotic mediator. Our results suggest that NaSH as an exogenous H2S donor could significantly reduce EBI induced by SAH.

Glycyrrhizic acid confers neuroprotection after subarachnoid hemorrhage via inhibition of high mobility group box-1 protein: A hypothesis for novel therapy of subarachnoid hemorrhage

Subarachnoid hemorrhage usually results in poor clinical outcome and devastating neurological deficits. The early brain injury and delayed vasospasm after subarachnoid hemorrhage (SAH) are involved in the poor prognosis to the patients, while the mechanisms have not been well elucidated. Previous studies found an up-regulation of Toll-like receptor 4 (TLR4), inflammatory factors and high-mobility group box 1 (HMGB1) in the cortex after SAH. Increased inflammatory response contributes to the early brain injury and delayed vasospasm after SAH. Moreover, we found that the inflammatory response could be induced and amplified following recombinant HMGB1 (rHMGB1) addition in cultured neurons. Based on the latest researches in this field, we raised a hypothesis that HMGB1, a prototypical member of damage-associated molecular pattern (DAMP) family, could be passively released from the damaged neuroglia cells and hemotocyte lysis after SAH. Extracellular HMGB1 initiated the inflammation through its receptors. The inflammatory mediators then acted on the neurocytes to make them actively release HMGB1 continuously, manifesting an double phases. HMGB1 might be the key factor to induce sterile inflammation, and thus be one of the origin of early brain injury and delayed vasospasm after SAH. Inhibition of extracellular HMGB1 activities might be a novel therapeutic target for SAH to reduce the damaging inflammatory response. Glycyrrhizic acid (GA) which was extracted from liquorice and confirmed as a nature inhibitor of HMGB1 with little side-effects could inhibit extracellular HMGB1 cytokine activities and reduce the level of inflammatory response, thus alleviating early brain injury and cerebrovasospasm. GA might be a new novel therapy of SAH for better outcomes.

Exploring the use of Estrogen &amp; Progesterone Replacement Therapy in Subarachnoid Hemorrhage

The hypothesis that alterations in hormone levels can impact on subarachnoid hemorrhage (SAH) is rapidly gaining momentum. Specifically, the concept that post-menopausal women are more susceptible to the condition has convinced many of the protective roles of estrogen and progesterone. Here we review the mechanisms of their actions and the potential for estrogen and progesterone replacement therapy in subarachnoid hemorrhage. Searches were performed using PubMed with the search terms "subarachnoid hemorrhage", "estrogen", "progesterone "treatment", "management", "cerebral aneurysm", and "vasospasm" from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed. In conclusion, there is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature.

The efficacy of fasudil in the prevention of cerebral vasospasm after neural interventional therapy

Objective To observe the clinical efficacy of fasudil in the prevention of cerebral vasospasm after neural interventional therapy.Methods 75 patients undergoing interventional therapy for subarachnoid hemorrhage were randomly divided into two groups.The study group ( n =38 ) received fasudil hydrochloride of 30mg thrice daily for 2weeks,while the control group ( n=37 ) received intravenous nimodipine of I mg/h.The total effectiveness rate was observed and compared between the two groups.Results The total effectiveness rate of treatment group was higher in the study group than in the control group ( 86.8％ vs.67.6％,P ＜ 0.05 ).No serve adverse reactions occurred during the treat ment.C onclusions Therapy with fasudil is efficacious and safe in the prevention of subarachnoid hemorrhage after neural interventional therapy and is worth popularizing clinically. Key words: Fasudil; Cerebral vasospasm; Subarachnoid hemorrhage

Cerebral watershed hypoperfusion in subarachnoid hemorrhage: computed tomography perfusion analysis

A better understanding of the pathophysiology of vasospasm-induced delayed cerebral ischemia and earlier detection of hypoperfusion before ischemic injury are needed to guide therapy in subarachnoid hemorrhage (SAH). The cerebrovascular physiology of the major arterial territories differs from that of the watershed zones (WZs) in a way that would suggest a differential topographic sensitivity of the brain to vasospasm. The primary end point of the study was to investigate the vasospasm-induced hypoperfusion in relation to cerebrovascular topography and timing from the onset of SAH. Forty-one patients were prospectively enrolled and scheduled for perfusion-weighted (PW) CT at 3 time points (≤ 3 days, Days 4-8, and Days 9-15 after SAH). Perfusion-weighted CT maps were visually assessed for side-to-side perfusion asymmetry. The PW CT topographic pattern was categorized into absence of asymmetry, WZ, and vascular territory hypoperfusion. Perfusion-weighted CT revision was performed by investigators blinded to clinical information. The null hypothesis for the primary end point was that there would be no difference in hypoperfusion space-time distribution among the different vascular territories. Multivariate logistic regression and Cox proportional hazards modeling were used for statistical analysis. Delayed cerebral ischemia occurred in 26 patients and its predicting variables were increasing age (p = 0.045), Fisher grade (p = 0.007), and hypoperfusion on the PW CT performed within the 1st 72 hours after SAH (p = 0.004). The timing of the PW CT with respect to the day of SAH affected the topographic pattern of hypoperfusion: watershed-zone hypoperfusion was more common within the first 3 days after SAH (p = 0.018), while the proportion of territorial hypoperfusion increased subsequently. Among the different covariates, a young age was independently associated with a higher risk of developing hypoperfusion in the WZs (p = 0.02). This study suggests the existence of a cerebral topographic heterogeneity to the hemodynamic effects of SAH and differential pathogenetic mechanisms of hypoperfusion according to timing, age, and brain topography. Hypoperfusion in the WZs may be an early precursor to more profound ischemic events. The PW CT detection of such brain-sensitive zones could offer a warning signal of the early hemodynamic effects of SAH and cerebral vasospasm.

017 Preventing strokes from vasospasm and heparin induced thrombocytopenia type II: nicardipine, milrinone, angioplasty and Argtroban

Purpose: To investigate the use of Argtroban in patients at risk for heparin induced thrombocytopenia type II (HIT) during intra-arterial (IA) therapy for subarachnoid hemorrhage (SAH) related vasospasm. Methods and...

Arginine Vasopressin as a Supplementary Vasopressor in Refractory Hypertensive, Hypervolemic, Hemodilutional Therapy in Subarachnoid Hemorrhage

Hypertensive, hypervolemic, and hemodilutional (HHH) therapy for vasospasm in subarachnoid hemorrhage (SAH) refractory to phenylephrine requires high doses of catecholamines, leading to adverse adrenergic effects. Arginine vasopressin (AVP) has been shown to stabilize advanced shock states while facilitating reduction of catecholamine doses, but its use has never been reported in SAH. In this retrospective study, we investigated the hemodynamic effects and feasibility of supplementary AVP in refractory HHH therapy in SAH. Hemodynamic response (mean arterial pressure [MAP], heart rate, central venous pressure, cardiac index, systemic vascular resistance index, and end diastolic volume index) to a supplementary AVP infusion (0.01-0.04 IU/minute) was recorded within the first 24 hours in 22 patients. Secondary endpoints (serum sodium concentration, incidence of vasospasm, and intracranial pressure [ICP]) were compared to controls on HHH therapy with phenylephrine alone. After initiation of AVP, MAP increased significantly compared to baseline. Phenylephrine doses decreased significantly, whereas other hemodynamic parameters remained stable. Serum sodium concentrations decreased similarly in both groups (-5 +/- 7 mmol/L versus -6 +/- 4 mmol/L; p = 0.25). No detrimental effects on vasospasm incidence or ICP and cerebral perfusion pressure were noted. AVP may be considered as an alternative supplementary vasopressor in refractory HHH therapy with phenylephrine in SAH. Although we did not observe any deleterious effect of AVP on cerebral circulation, close observation for development of cerebral vasospasm should be undertaken, until it is clearly demonstrated that AVP has no adverse effects on regional cerebral blood flow and symptomatic cerebral vasospasm. Our limited data suggest that low-dose AVP does not cause brain edema, but further study is merited.

Monitoring Hypervolemic-hemodilution And Hypertensive Therapy In Subarachnoid Hemorrhage

Introduction: Prophylactic hypervolemic-hemodilution-hypertensive (HHH) therapy in subarachnoid hemorrhage (SAH) may be beneficial in reducing delayed ischaemia after early aneurysm clipping. The aim of this study was to assess the correlation among pulmonary artery catheter (PAC) measurements, effectiveness of HHH-therapy and mean flow velocity (MFV) in the middle cerebral artery (MCA) by transcranial Doppler. Methods: We recorded Hunt-Hess classification, hematocrit, hemodynamic and PAC values, bilateral MFV in the MCA and Rankin scale in 37 ICU patients with SAH and no vasospasm (MFV 160 and wedge pressure (PCWP) > 12, moderate when only SBP > 160 or PCWP >12, and ineffective when SBP < 160 and PCWP < 12. Fisher's t test and multiple regression analysis were used for data analysis, p <0.05 was significant. Results: An effective prophylactic HHH-therapy did not reduce occurrence of vasospasm. Outcome did not correlate with clinical state on admission or effectiveness of HHH-therapy. A constantly elevated systemic vascular resistance index (SVRI) was associated with a good outcome while the combination of high MFV in MCA and decline in SVRI with poor outcome (p<0.05). Multiple regression analysis showed that SVRI and hematocrit explained 46% of variance of MFV in patients without vasospasm (MFV <120 cm/s, n=16). Conclusion: Our data demonstrate a correlation among SVRI, hematocrit and MFV. The differences in the outcome between the group where SVRI and MFV where moving in the same directions and the patient group where SVRI and MFV where moving in the opposite direction may be interpreted as early sign of vasospasm and may help to differentiate elevated MFV due to vasospasm (SVRI low) and elevated MFV due to effective HHH therapy (SVRI high). Differences in the outcome between the high and low SVRI may also be due to co-morbidities associated with low vascular resistance in the poor outcome group (e.g. sepsis, SIRS).

Monitoring Hypervolemic-hemodilution And Hypertensive Therapy In Subarachnoid Hemorrhage

Introduction: Prophylactic hypervolemic-hemodilution-hypertensive (HHH) therapy in subarachnoid hemorrhage (SAH) may be beneficial in reducing delayed ischaemia after early aneurysm clipping. The aim of this study was to assess the correlation among pulmonary artery catheter (PAC) measurements, effectiveness of HHH-therapy and mean flow velocity (MFV) in the middle cerebral artery (MCA) by transcranial Doppler. Methods: We recorded Hunt-Hess classification, hematocrit, hemodynamic and PAC values, bilateral MFV in the MCA and Rankin scale in 37 ICU patients with SAH and no vasospasm (MFV 160 and wedge pressure (PCWP) > 12, moderate when only SBP > 160 or PCWP >12, and ineffective when SBP < 160 and PCWP < 12. Fisher's t test and multiple regression analysis were used for data analysis, p <0.05 was significant. Results: An effective prophylactic HHH-therapy did not reduce occurrence of vasospasm. Outcome did not correlate with clinical state on admission or effectiveness of HHH-therapy. A constantly elevated systemic vascular resistance index (SVRI) was associated with a good outcome while the combination of high MFV in MCA and decline in SVRI with poor outcome (p<0.05). Multiple regression analysis showed that SVRI and hematocrit explained 46% of variance of MFV in patients without vasospasm (MFV <120 cm/s, n=16). Conclusion: Our data demonstrate a correlation among SVRI, hematocrit and MFV. The differences in the outcome between the group where SVRI and MFV where moving in the same directions and the patient group where SVRI and MFV where moving in the opposite direction may be interpreted as early sign of vasospasm and may help to differentiate elevated MFV due to vasospasm (SVRI low) and elevated MFV due to effective HHH therapy (SVRI high). Differences in the outcome between the high and low SVRI may also be due to co-morbidities associated with low vascular resistance in the poor outcome group (e.g. sepsis, SIRS).

Diffusion- and perfusion-weighted imaging in vasospasm after subarachnoid hemorrhage.

Better measures of cerebral tissue perfusion and earlier detection of ischemic injury are needed to guide therapy in subarachnoid hemorrhage (SAH) patients with vasospasm. We sought to identify tissue ischemia and early ischemic injury with combined diffusion-weighted (DW) and hemodynamically weighted (HW) MRI in patients with vasospasm after SAH. Combined DW and HW imaging was used to study 6 patients with clinical and angiographic vasospasm, 1 patient without clinical signs of vasospasm but with severe angiographic vasospasm, and 1 patient without angiographic spasm. Analysis of the passage of an intravenous contrast bolus through brain was used to construct multislice maps of relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and tissue mean transit time (tMTT). We hypothesize that large HW imaging (HWI) abnormalities would be present in treated patients at the time they develop neurological deficit due to vasospasm without matching DW imaging (DWI) abnormalities. Small, sometimes multiple, ischemic lesions on DWI were seen encircled by a large area of decreased rCBF and increased tMTT in all patients with symptomatic vasospasm. Decreases in rCBV were not prominent. MRI hemodynamic abnormalities occurred in regions supplied by vessels with angiographic vasospasm or in their watershed territories. All patients with neurological deficit showed an area of abnormal tMTT much larger than the area of DWI abnormality. MRI images were normal in the asymptomatic patient with angiographic vasospasm and the patient with normal angiogram and no clinical signs of vasospasm. We conclude that DW/HW MRI in symptomatic vasospasm can detect widespread changes in tissue hemodynamics that encircle early foci of ischemic injury. With additional study, the technique could become a useful tool in the clinical management of patients with SAH.

Monitoring of hypervolemic hemodilution and hypertensive (HHH) therapy in subarachnoid hemorrhage (SAH) patients with pulmonary artery catheter (PAC)

Monitoring of hypervolemic hemodilution and hypertensive (HHH) therapy in subarachnoid hemorrhage (SAH) patients with pulmonary artery catheter (PAC)

Antifibrinolytic therapy in subarachnoid hemorrhage caused by ruptured intracranial aneurysm.

There are 25 published studies on the treatment with antifibrinolytic agents of subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysm. Twelve of these studies were uncontrolled and, except for one, all reported reduced incidence of rebleeding. Of 13 controlled studies, 9 were randomized, and 3 were also double-blind. In 7, reported decrease in rebleeding was reported, but only 4 showed decreased mortality. Three studies showed no effect, and three reported a higher incidence of rebleeding in treated patients. Discrepancies may be due to the multiple clinical variables of SAH and to flaws in methodology; nevertheless, the data fail to demonstrate that antifibrinolytic therapy alters the natural history of the disease.